Carcinogens Still Vex Drug Industry Years After Recalls Began
(Bloomberg) -- Years after millions of blood-pressure pills were recalled for containing potentially cancer-causing chemicals, U.S. regulators are still grappling with curbing contaminants that keep turning up in tainted drugs.
A task force of Food and Drug Administration chemists, toxicologists and analytical lab staff have been meeting regularly since 2018 to find out how the chemicals, called nitrosamines, get into drugs, how widespread the issue is -- and how to eliminate them from medicines.
So far, that target has proved elusive.
“Despite the nearly two and a half years into this contamination issue, we have, still, many ongoing challenges,” Sruthi King, associate director of pharmacology and toxicology in the FDA’s generic drugs office, said at a public meeting involving some members of the task force in March.
While the recalls have slowed, contamination episodes persist. In recent weeks, a nitrosamine was found in a popular smoking-cessation drug and a widely used diabetes treatment. Two tuberculosis therapies were found to be tainted with nitrosamines last year.
To try to prevent shortages, the FDA adopted temporary nitrosamine limits in 2018. It allowed exposure to one of the most common of the class of chemicals, NDMA, of 96 nanograms a day, and set caps for similar agents. The curbs are based on levels not exceeding a theoretical excess cancer risk of one in 100,000.
If a drug had nitrosamines above the limits, it could be recalled. In September, the agency said those initial thresholds represented its official guidance for nitrosamine levels.
It’s unclear if the agency’s early goal of expunging nitrosamines from pills is attainable. Complicated manufacturing processes and a complex global supply chain for pharmaceutical ingredients are making it difficult to determine all the ways drugs can be contaminated.
While some industries that faced similar problems were able to solve them with production fixes, others have had to accept the possibility that embedded in their products is a remote risk of cancer.
Nitrosamines can be reduced or prevented from forming in some pharmaceuticals, said Jeremy Kahn, an FDA spokesman.
“For other drugs, the FDA has determined that the presence of a nitrosamine is due to factors that warrant limiting the amount in the final drug product to levels that will not result in an unacceptable risk over a lifetime of use,” he said.
With better detection techniques, more companies are finding products that contain low levels of nitrosamines, FDA chemists and toxicologists said at the March meeting. Those occurrences often aren’t made public since they don’t meet the recall threshold.
Drugmakers are “being surprised quite frequently” by the results of FDA-requested testing of their products, Deborah Johnson, an agency chemist, told the March workshop, while not naming specific companies or medications.
The FDA didn’t respond to questions about which drugs have tested positive for nitrosamine levels below the agency’s acceptable limit.
Regulators are weighing the feasibility of eliminating impurities against the medical necessity of a drug, Robert Dorsam, a pharmacologist and toxicologist in the FDA’s Office of Generic Drugs, said at the meeting.
“We’re looking more heavily at that risk-benefit scenario for a particular drug and a particular population,” Dorsam said.
Drugmakers aren’t the first industry to deal with nitrosamines. Decades ago, a similar problem jolted brewers.
In 1979, researchers at the German Cancer Research Centre discovered that beer contained NDMA, one of the researchers, Gerhard Eisenbrand, said in an interview.
NDMA formed when malt, the source of sugar in beer, was dried in high-heat kilns and browned. Natural nitrous oxide in the hot air formed a reaction that created NDMA, Eisenbrand said.
The industry changed the process by converting to indirect-heat kilns and largely eliminated the carcinogen, Eisenbrand said. German food chemist Dirk Lachenmeier wrote in Brewing Science in 2007 that the “almost complete prevention of NDMA in beer can be seen as a success story of the brewing industry.”
Nitrosamines also show up in meat. While producers have tried to lower consumers’ exposure, the carcinogens remain.
The FDA says a pound of bacon contains as much as 354 nanograms of NDMA, roughly three and a half times the daily limit for drugs. Few people eat a pound of bacon at a sitting, but most who take medication for a chronic disease do so once a day or more for life.
Eisenbrand said that while it would be easier to remove nitrosamines from drugs, he would expect it to take time, and the industry could draw on what other businesses have learned.
“If steps can be taken to completely avoid the presence of them, of nitrosamines, I think that’s better for everybody but as we all know that’s not always possible,” Timothy McGovern, associate director for pharmacology and toxicology in the FDA’s drug center, said during the March FDA task force meeting.
Indeed, tainted drugs keep surfacing. Pfizer Inc. said last week that it halted distribution of smoking-cessation therapy Chantix after detecting elevated nitrosamines. It is recalling an unspecified number of pills.
Pfizer found Chantix that was contaminated with a nitrosamine called N-nitroso-varenicline, the company said. Pfizer said the nitrosamine may form from a chemical reaction involving the drug’s active ingredient, varenicline.
Last month, India-based Cadila Healthcare Ltd. recalled extended-release versions of the diabetes drug metformin after finding that it contained NDMA. It was the 17th metformin recall related to NDMA in a year.
Charles White, a professor at the University of Connecticut’s School of Pharmacy, wrote a commentary in the Journal of the American Medical Association this year listing drugs he thought had the potential to form NDMA.
One was migraine medication sumatriptan, which GlaxoSmithKline Plc sells under the name Imitrex. Testing by the company found levels of nitrosamines below the acceptable limit, a spokeswoman said. Glaxo hasn’t identified any further action that needs to be taken, she said.
Ten million prescriptions for sumatriptan, both brand and generic, were written last year in the U.S., according to Bloomberg data.
Adding to the difficulty in finding a simple fix, the circumstances under which drugs have become tainted vary.
NDMA showed up in some blood-pressure pills called angiotensin II receptor blockers, or ARBs, because the solvent used to break down ingredients wasn’t properly eliminated, yielding a reaction that formed the carcinogen, the FDA has said.
Johnson, the FDA chemist, said at the March meeting that other routes of formation have also been found, including some that, like malting, involve extracting moisture. She said she doesn’t think “we still truly have a complete understanding of all the possible ways” the impurities could form.
In the case of digestive drug ranitidine, sold under the brand Zantac, the FDA asked companies to take pills off the market last year after they were found to form NDMA over time or in high temperatures.
Even within drug groups the risks aren’t uniform: The FDA said in 2018 that there were ARBs that didn’t contain detectable nitrosamines. Later, the agency pointed to quality-control problems that could have allowed the contamination to happen at some companies but not others.
Pharmaceutical companies have largely outsourced drug production, especially for cheaper generic medications, to countries where the FDA has tended to find more quality-control violations, including sanitation issues and manipulation of data linked to routine product testing.
The contamination of the recalled blood-pressure pills showed up specifically in their active ingredients, most of which were made in China and India.
Additionally, an agency database shows a large majority of recalled metformin was manufactured in India.
For active pharmaceutical ingredient production for generic drugs, 87% of manufacturers are located outside of the U.S., including 29% in India, 27% in the European Union and 16% in China, according to a supply chain report released last month by the White House.
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